Inhibition of Pneumococcal Carriage in Mice by Subcutaneous Immunization with Peptides from the Common Surface Protein Pneumococcal Surface Adhesin A

Johnson, Scott E.; Dykes, Janet K.; Jue, Danny L.; Sampson, Jaquelyn S.; Carlone, George M.; Ades, Edwin W.

doi:10.1086/338928

Cited by 48 publications

(21 citation statements)

References 46 publications

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“…Three out of four prominent bands recognized by cross-reactive antibody on May 9, 2018 by guest http://iai.asm.org/ were found to be surface-associated proteins. Each of these three proteins, PspA, PpmA, and PsaA, has been previously proposed as a vaccine candidate or shown to induce protective responses when given as a purified protein together with an adjuvant (6,12,37), although evidence for cross-protection against colonization elicited by these purified antigens is more limited (6,22). Our results provide an unbiased confirmation of the potential of each of these antigens to induce a crossreactive immune response.…”

Section: Discussionsupporting

confidence: 68%

Identification of the Targets of Cross-Reactive Antibodies Induced byStreptococcus pneumoniaeColonization

Roche

Weiser

2010

Infect Immun

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Much of the efficacy of current pneumococcal conjugate vaccines lies in their ability to decrease carriage of vaccine serotypes in the population. Novel and more-broadly acting vaccines would also need to target carriage in order to be as effective. We have previously shown that model murine carriage of Streptococcus pneumoniae can elicit antibody-dependent immunity and can protect against a virulent heterologous challenge strain. This study set out to identify S. pneumoniae surface antigens that may elicit cross-reactive antibodies following colonization. Western blot analysis using sera from colonized mice identified the previously characterized immunogens pneumococcal surface protein A (PspA), putative proteinase maturation protein A (PpmA), and pneumococcal surface adhesin A (PsaA) as such antigens. Using flow cytometry, PspA was found to be the major target of surface-bound cross-reactive IgG in sera from TIGR4⌬cps-colonized mice, with a modest contribution from PpmA and none from PsaA. In human sera, however, only mutants lacking PpmA were shown to have reduced binding of surface IgG compared to wild-type strains, suggesting that prior exposure to S. pneumoniae in humans may induce PpmA antibodies. We also investigated if cross-reactive antibodies induced by these antigens may be cross-protective against carriage. Despite the immunogenicity of PspA, PpmA, and PsaA, mice were still protected following colonization with mutants lacking these antigens, suggesting they are not necessary for cross-protection induced by carriage. Our findings suggest that a whole-organism approach may be needed to broadly diminish carriage.

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Section: Discussionsupporting

confidence: 68%

Identification of the Targets of Cross-Reactive Antibodies Induced byStreptococcus pneumoniaeColonization

Roche

Weiser

2010

Infect Immun

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“…It is important to note that, although we have demonstrated that PsaA and PpmA are poor vaccine targets for protection against systemic pneumococcal infection (at least under the present experimental conditions) on the basis of their inaccessibility to antibodies, other studies have demonstrated that mucosal immunization of mice with PsaA is highly protective against pneumococcal carriage (5,7,11,23). The exact mechanisms of protection against pneumococcal carriage afforded by immunization with PsaA have not yet been elucidated.…”

Section: Discussionmentioning

confidence: 68%

Relationship between Surface Accessibility for PpmA, PsaA, and PspA and Antibody-Mediated Immunity to Systemic Infection by Streptococcus pneumoniae

et al. 2005

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Antibodies to capsular polysaccharide (PS) are protective against systemic infection by Streptococcus pneumoniae, but the large number of pneumococcal serogroups and the age-related immunogenicity of pure PS limit the utility of PS-based vaccines. In contrast, cell wall-associated proteins from different capsular serotypes can be cross-reactive and immunogenic in all age groups. Therefore, we evaluated three pneumococcal proteins with respect to relative accessibility to antibody, in the context of intact pneumococci, and their ability to elicit protection against systemic infection by encapsulated S. pneumoniae. Sequences encoding pneumococcal surface adhesin A (PsaA), putative protease maturation protein A (PpmA), and the N-terminal region of pneumococcal surface protein A (PspA) from S. pneumoniae strain A66.1 were cloned and expressed in Escherichia coli. The presence of genes encoding PsaA, PpmA, and PspA in 11 clinical isolates was examined by PCR, and the expression of these proteins by each strain was examined by Western blotting with antisera raised to the respective recombinant proteins. We used flow cytometry to demonstrate that PspA was readily detectable on the surface of the pneumococcal strains analyzed, whereas PsaA and PpmA were not. Consistent with these observations, mice with passively or actively acquired antibodies to PspA or type 3 PS were equivalently protected from homologous systemic challenge with type 3 pneumococci, whereas mice with passively or actively acquired antibodies to PsaA or PpmA were not effectively protected. These experiments support the hypothesis that the extent of protection against systemic pneumococcal infection is influenced by target antigen accessibility to circulating host antibodies.

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“…Previous studies from several laboratories have shown that PsaA immunization is most effective against nasopharyngeal colonization (18,35,37). However, the effectiveness of PsaA immunization against systemic pneumococcal challenges varies in different studies (14,43).…”

Section: Discussionmentioning

confidence: 99%

Intranasal Vaccination with Chitosan-DNA Nanoparticles Expressing Pneumococcal Surface Antigen A Protects Mice against Nasopharyngeal Colonization by Streptococcus pneumoniae

Dai

Wang

et al. 2011

Clin Vaccine Immunol

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Streptococcus pneumoniae is a respiratory pathogen, and mucosal immune response plays a significant role in the defense against pneumococcal infections. Thus, intranasal vaccination may be an alternative approach to current immunization strategies, and effective delivery systems to mucosal organism are necessary. In this study, BALB/c mice were immunized intranasally with chitosan-DNA nanoparticles expressing pneumococcal surface antigen A (PsaA). Compared to levels in mice immunized with naked DNA or chitosan-pVAX1, anti-PsaA IgG antibody in serum and anti-IgA antibody in mucosal lavages were elevated significantly in mice immunized with chitosan-psaA. The balanced IgG1/IgG2a antibody ratio in serum, enhanced gamma interferon (IFN-␥) and IL-17A levels in spleen lymphocytes, and mucosal washes of mice immunized with chitosan-psaA suggested that cellular immune responses were induced. Furthermore, significantly fewer pneumococci were recovered from the nasopharynx of mice immunized with chitosan-psaA than for the control group following intranasal challenge with ATCC 6303 (serotype 3). These results demonstrated that mucosal immunization with chitosan-psaA may successfully generate mucosal and systemic immune responses and prevent pneumococcal nasopharyngeal colonization. Hence, a chitosan-DNA nanoparticle vaccine expressing pneumococcal major immunodominant antigens after intranasal administration could be developed to prevent pneumococcal infections.

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Inhibition of Pneumococcal Carriage in Mice by Subcutaneous Immunization with Peptides from the Common Surface Protein Pneumococcal Surface Adhesin A

Cited by 48 publications

References 46 publications

Identification of the Targets of Cross-Reactive Antibodies Induced byStreptococcus pneumoniaeColonization

Identification of the Targets of Cross-Reactive Antibodies Induced byStreptococcus pneumoniaeColonization

Relationship between Surface Accessibility for PpmA, PsaA, and PspA and Antibody-Mediated Immunity to Systemic Infection by Streptococcus pneumoniae

Intranasal Vaccination with Chitosan-DNA Nanoparticles Expressing Pneumococcal Surface Antigen A Protects Mice against Nasopharyngeal Colonization by Streptococcus pneumoniae

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